This invention relates to novel cycloalkenyl substituted compounds, processes for the preparation thereof, the use thereof in treating cytokine mediated diseases and pharmaceutical compositions for use in such therapy.
Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Regardless of the nature of the cell surface receptor (e. g. protein tyrosine kinase or seven-transmembrane G-protein coupled), protein kinases and phosphatases along with phopholipases are the essential machinery by which the signal is further transmitted within the cell [Marshall, J. C. Cell, 80, 179-278 (1995)]. Protein kinases can be categorized into five classes with the two major classes being, tyrosine kinases and serine/threonine kinases depending upon whether the enzyme phosphorylates its substrate(s) on specific tyrosine(s) or serine/threonine(s) residues [Hunter, T., Methods in Enzyrnology (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B. M.; eds. vol. 200, Academic Press; San Diego, 1991].
For most biological responses, multiple intracellular kinases are involved and an individual kinase can be involved in more than one signaling event. These kinases are often cytosolic and can translocate to the nucleus or the ribosomes where they can affect transcriptional and translational events, respectively. The involvement of kinases in transcriptional control is presently much better understood than their effect on translation as illustrated by the studies on growth factor induced signal transduction involving MAP/ERK kinase [Marshall, C. J. Cell, 80, 179 (1995); Herskowitz, I. Cell, 80, 187 (1995); Hunter, T. Cell, 80, 225 (1995);Seger, R., and Krebs, E. G. FASEB J., 726-735 (1995)].
While many signaling pathways are part of cell homeostasis, numerous cytokines (e.g., IL-1 and TNF) and certain other mediators of inflammation (e.g., COX-2, and iNOS) are produced only as a response to stress signals such as bacterial lippopolysaccharide (LPS). The first indications suggesting that the signal transduction pathway leading to LPS-induced cytokine biosynthesis involved protein kinases came from studies of Weinstein [Weinstein, et al., J. Immunol. 151, 3829(1993)] but the specific protein kinases involved were not identified. Working from a similar perspective, Han [Han, et al., Science 265, 808(1994)] identified murine p38 as a kinase which is tyrosine phosphorylated in response to LPS. Definitive proof of the involvement of the p38 kinase in LPS-stimulated signal transduction pathway leading to the initiation of proinflammatory cytokine biosynthesis was provided by the independent discovery of p38 kinase by Lee [Lee; et al., Nature, 372, 739(1994)] as the molecular target for a novel class of anti-inflammatory agents. The discovery of p38 (termed by Lee as CSBP 1 and 2) provided a mechanism of action of a class of anti-inflammatory compounds for which SKandF 86002 was the prototypic example. These compounds inhibited IL-1 and TNF synthesis in human monocytes at concentrations in the low uM range [Lee, et al., Int. J. Immunopharmac. 10(7), 835(1988)] and exhibited activity in animal models which are refractory to cyclooxygenase inhibitors [Lee; et al., Annals N. Y. Acad. Sci., 696, 149(1993)].
It is now firmly established that CSBP/p38 is a one of several kinases involved in a stress-response signal transduction pathway which is parallel to and largely independent of the analogous mitogen-activated protein kinase (MAP) kinase cascade (FIG. 1). Stress signals, including LPS, pro-inflammatory cytokines, oxidants, UV light and osmotic stress, activate kinases upstream from CSBP/p38 which in turn phosphorylate CSBP/p38 at threonine 180 and tyrosine 182 resulting in CSBP/p38 activation. MAPKAP kinase-2 and MAPKAP kinase-3 have been identified as downstream substrates of CSBP/p38 which in turn phosphorylate heat shock protein Hsp 27 (FIG. 2). It is not yet known whether MAPKAP-2, MAPKAP-3, Mnk1 or Mnk2 are involved in cytokine biosynthesis or alternatively that inhibitors of CSBP/p38 kinase might regulate cytokine biosynthesis by blocking a yet unidentified substrate downstream from CSBP/p38 [Cohen, P. Trends Cell Biol., 353-361(1997)].
What is known, however, is that in addition to inhibiting IL-1 and TNF, CSBP/p38 kinase inhibitors (SKandF 86002 and SB 203580) also decrease the synthesis of a wide variety of pro-inflammatory proteins including, IL-6, IL-8, GM-CSF and COX-2. Inhibitors of CSBP/p38 kinase have also been shown to suppress the TNF-induced expression of VCAM-1 on endothelial cells, the TNF-induced phosphorylation and activation of cytosolic PLA2 and the IL-1-stimulated synthesis of collagenase and stromelysin. These and additional data demonstrate that CSBP/p38 is involved not only cytokine synthesis, but also in cytokine signaling [CSBP/P38 kinase reviewed in Cohen, P. Trends Cell Biol., 353-361(1997)].
Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, e.g., Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter""s syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic xcex2 cells [review of the biological activities which have been attributed to IL-1 Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985)].
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia, secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn""s disease, ulcerative colitis, or pyresis.
Interleukin-8 (IL-8) is a chemotactic factor produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF, or lipopolysachharide (LPS). IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increased in IL-8 production (which is responsible for chemotaxis of neutrophil into the inflammatory site) would benefit by compounds which are suppressive of IL-8 production.
IL-1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
Inhibition of signal transduction via CSBP/p38, which in addition to IL-1, TNF and IL-8 described above is also required for the synthesis and/or action of several additional pro-inflammatory proteins (i.e., IL-6, GM-CSF, COX-2, collagenase and stromelysin), is expected to be a highly effective mechanism for regulating the excessive and destructive activation of the immune system. This expectation is supported by the potent and diverse anti-inflammatory activities described for CSBP/p38 kinase inhibitors [Badger, et al., J. Pharm. Exp. Thera 279 (3): 1453-1461.(1996); Griswold, et al, Pharmacol. Comm. 7, 323-229 (1996)].
There remains a need for treatment, in this field, for compounds which are cytokine suppressive anti-inflammatory drugs, i.e. compounds which are capable of inhibiting the CSBP/p38/RK kinase.
This invention relates to the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutically acceptable diluent or carrier.
This invention relates to a method of treating a CSBP/RK/p38 kinase mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
This invention also relates to a method of inhibiting cytokines and the treatment of a cytokine mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
This invention more specifically relates to a method of inhibiting the production of IL-1 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
This invention more specifically relates to a method of inhibiting the production of IL-8 in a mammal in need thereof which comprises administering to aid mammal an effective amount of a compound of Formula (I).
This invention more specifically relates to a method of inhibiting the production of TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
Accordingly, the present invention provides for a compound of the formula: 
wherein
R1 is 4-pyridyl, 4-pyrimidinyl, 4-pyridazinyl, 1,2,4-triazin-5-yl, 4-quinolyl, 6-isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl ring, which ring is optionally substituted independently one to three times with Y, NHRa, optionally substituted C1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, optionally substituted C1-4 alkylsulfinyl, CH2OR12, amino, mono and di- C1-6 alkyl substituted amino, N(R10)C(O)Rb, N(R10)S(O)2Rd, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15;
Y is X1xe2x80x94Ra;
X1 is sulfur or oxygen;
Ra is C1-6 alkyl, aryl, arylC1-6 alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, or heteroarylC1-6 alkyl moiety, wherein each of these moieties may be optionally substituted;
Rb is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4 alkyl, heterocyclyl, or heterocyclylC1-4 alkyl;
Rd is C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4 alkyl, heterocyclyl, or heterocyclylC1-4 alkyl;
Rg is independently hydrogen or R2;
n is 0, or an integer having a value of 1 to 10;
v is 0, or an integer having a value of 1 or 2;
m is 0, or the integer having a value of 1 or 2;
mxe2x80x2 is an integer having a value of 1 or 2,
mxe2x80x3 is 0, or an integer having a value of 1 to 5;
s is an integer having a value of 1 to 5;
t is 0, or an integer having a value of 1, 2 or 3;
R2 is independently hydrogen, (CR10R23)nOR9, (CR10R23)nOR11, C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl C1-10 alkyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, heterocyclyl, heterocyclylC1-10 alkyl, (CR10R23)nS(O)mR18, (CR10R23)nNHS(O)2R18, (CR10R23)nNR13R14, (CR10R23)nNO2, (CR10R23)nCN, (CR10R23)nS(O)mxe2x80x2NR13R14, (CR10R23)nC(Z)R11, (CR10R23)nOC(Z)R11(CR10R23)nC(Z)OR11, (CR10R23)nC(Z)NR13R14, (CR10R23)nC(Z)NR11OR9, (CR10R23)nNR10C(Z)R11, (CR10R23)nNR10C(Z)NR13R14, (CR10R23)nN(OR6)C(Z)NR13R14, (CR10R23)nN(OR6)C(Z)R11, (CR10R23)nC(xe2x95x90NOR6)R11, (CR10R23)nNR10C(xe2x95x90NR19)NR13R14, (CR10R23)nOC(Z)NR13R14, (CR10R23)nNR10C(Z)NR13R14, (CR10R23)nNR10C(Z)OR10, 5-(R18)-1,2,4-oxadizaol-3-yl or 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the cycloalkyl, cycloalkyl alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl may be optionally substituted;
R3 is heterocyclyl, heterocyclylC1-10 alkyl or R8;
R4 is phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, which is optionally substituted by one to three substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR7R17, C(Z)OR16, (CR10R20)vCOR12, SR5, S(O)R5, OR12, halo-substituted-C1-4 alkyl, C1-4alkyl, ZC(Z)R12, NR10C(Z)R16, or (CR10R20)vNR10R20 and which, for other positions of substitution, is halogen, cyano, nitro, phenyl, C(Z)NR13R14, C(Z)OR3, (CR10R20)mxe2x80x3COR3, S(O)mR3, OR3, halosubstituted-C1-4 alkyl, C1-10 alkyl, ZC(Z)R3, optionally substituted phenyl, (CR10R20)mxe2x80x3NR10C(Z)R3, NR10S(O)mxe2x80x2R8, NR10S(O)mxe2x80x2NR7R17, or (CR10R20)mxe2x80x3NR13R14;
R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties SR5 being SNR7R17 and SOR5 being SOH;
R6 is hydrogen, a pharmaceutically acceptable cation, C1-10 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4 alkyl, heterocyclic, aroyl, or C1-10 alkanoyl;
R7 and R17 is each independently selected from hydrogen or C1-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulur or NR15;
R8 is C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, or (CR10R20)nNR13R14; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;
R9 is hydrogen, C(Z)R11 or optionally substituted C1-10 alkyl, S(O)2R18, optionally substituted aryl or optionally substituted arylC1-4 alkyl;
R10 and R20 is each independently selected from hydrogen or C1-4 alkyl;
R11 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10 alkyl, aryl, arylC1-10 alkyl, heteroaryl or a heteroarylC1-10 alkyl moiety, wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl or heterocyclylalkyl moieties may be optionally substituted;
R12 is hydrogen or R16;
R13 and R14 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9;
R15 is hydrogen, C1-4 alkyl or C(Z)xe2x80x94C1-4 alkyl;
R16 is C1-4 alkyl, halo-substituted-C1-4 alkyl, or C3-7 cycloalkyl;
R18 is C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylC1-10 alkyl, heterocyclyl, heterocyclyl-C1-10 alkyl, heteroaryl or a heteroarylalkyl moiety, wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl or heterocyclylalkyl moieties may be optionally substituted;
R19 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl;
R23 is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4 alkyl, heterocyclyl, or heterocyclylC1-4 alkyl moiety, all of which moieties may be optionally substituted;
Z is oxygen or sulfur;
or a pharmaceutically acceptable salt thereof.
The novel compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of cytokine inhibition or production. In particular, cytokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section, but in particular viral infections. Examples of such viruses include, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.
In Formula (I), suitable R1 moieties includes 4-pyridyl, 4-pyrimidinyl, 4-pyridazinyl, 1,2,4-triazin-5-yl, 4-quinolyl, 6-isoquinolinyl, 4-quinazolinyl, 1-iraidazolyl and 1-benzimidazolyl, of which the 4-pyridyl, 4-pyrimidinyl and 4-quinolyl are preferred. More preferred is a substituted 4-pyrimidinyl or substituted 4-pyridyl moiety, and most preferred is a substituted 4-pyrimidinyl ring. A preferred ring placement of the R1 substituent on the 4-pyridyl derivative is the 2-position, such as 2-methoxy-4-pyridyl. A preferred ring placement on the 4-pyrimidinyl ring is also at the 2-position, such as in 2-methoxy-pyrimidinyl.
The R1 moiety may be optionally substituted one or more times, independently, by suitable substituents. Such substituents include Y, NHRa, optionally substituted C1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, optionally substituted C1-4 alkylsulfinyl, CH2OR12, amino, mono and di-C1-6 alkyl substituted amino, N(R10)C(O)Rb; N(R10)S(O)2Rd; or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15.
Suitably Y is X1xe2x80x94Ra; and X1 is oxygen or sulfur, preferably oxygen.
Suitably, Ra is C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, or heteroarylC1-6alkyl, wherein each of these moieties may be optionallysubstituted as defined herein.
When the substituent is contains the Ra moiety, and Ra is aryl, it is preferably phenyl or naphthyl. When Ra is an aryl alkyl, it is preferably benzyl or napthylmethyl. When Ra is heterocyclic or heterocyclic alkyl moiety, the heterocyclic portion is preferably pyrrolindinyl, piperidine, morpholino, tetrahydropyran, tetrahydrothiopyranyl, tetrahydrothiopyran-sulfinyl, tetrahydrothio-pyransulfonyl, pyrrolindinyl, indole, or piperonyl. It is noted that the heterocyclic rings herein may contain unsaturation, such as in an indole ring. When Ra is a heteroaryl or heteroarylalkyl moiety it is as defined herein.
These Ra aryl, heterocyclic and heteroaryl rings may also be optionally substituted one or more times independently with halogen; C1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted alkyl, such as CF3; hydroxy; hydroxy substituted C1-4 alkyl; C1-4 alkoxy, such as methoxy or ethoxy; S(O)malkyl and S(O)m aryl (wherein m is 0, 1, or 2); C(O)OR11, such as C(O)C1-4 alkyl or C(O)OH moieties; C(O)R11; OC(O)Rc; Oxe2x80x94(CH2)sxe2x80x94Oxe2x80x94, such as in a ketal or dioxyalkylene bridge, and s is 1 to 3; amino; mono- and di-C1-6 alkylsubstituted amino, N(R10)C(O)Rb; N(R10)S(O)2Rd; C(O)NR10R20; S(O)2(CR10R20)tNR13R14 (wherein t is 0, or an integer of 1 to 3); cyano, nitro, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; aryl, such as phenyl; an optionally substituted arylalkyl, such as benzyl or phenethyl; aryloxy, such as phenoxy; or arylalkyloxy such as benzyloxy.
Suitably, Rb is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 alkyl, wherein all of which may be optionally substituted.
Suitably, Rc is hydrogen, optionally substituted C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 alkyl moiety, wherein all of which may be optionally substituted.
Suitably, Rd is C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 alkyl, wherein all of which may be optionally substituted.
When the Ra moiety is an alkyl group it may be optionally substituted as defined herein. Also the alkyl portion of the R1 substituents, the mono- and di-C1-6 alkyl amino moieties, may also be halo substituted.
Preferably, the Ra group is an alkyl, such as methyl, an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl.
When the R1 optional substituent group is N(R10)C(O) Rb, Rb is preferably a C1-6 alkyl; and R10 is preferably hydrogen. It is also recognized that all the Rb moieties, in particular the C1-6 alkyl group may be optionally substituted, preferably from one to three times as defined herein. Preferably Rb is C1-6 alkyl substituted with halogen, such as fluorine, as in trifluoromethyl or trifluroethyl.
Suitably, R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl ring. Preferably R4 is a phenyl or naphthyl ring.
Suitable substitutions for R4 when this is a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl moiety are one or three, preferably one to two, substituents each of which are independently selected from halogen, SR5, SOR5, OR12, CF3, or (CR10R20)vNR10R20, and for other positions of substitution on these rings preferred substitution is halogen, S(O)mR3, OR3, CF3, (CR10R20)mxe2x80x3NR13R14, NR10C(Z)R3 and NR10S(O)mxe2x80x2R8. Preferred substituents for the 4-position in phenyl and naphth-1-yl and on the 5-position in naphth-2-yl include halogen, especially fluoro and chloro, and SR5 and SOR5 wherein R5 is preferably a C1-2 alkyl, more preferably methyl; of which the fluoro and chloro is more preferred, and most especially preferred is fluoro. For all other substituents, in particular for the 3-position in phenyl and naphth-1-yl rings, the substituents are independently selected from halogen, especially fluoro and chloro; OR3, especially C1-4 alkoxy; CF3, NR10R20, such as amino; NR10C(Z)R3, especially NHCO(C1-10 alkyl); NR10S(O)mxe2x80x2R8, especially NHSO2(C1-10 alkyl); and SR3 and SOR3 wherein R3 is preferably a C1-2 alkyl, more preferably methyl.
When the phenyl ring is disubstituted, preferably it is two independent halogen moieties, such as fluoro and chloro, preferably di-chioro and more preferably in the 3, 4-position. It is also preferred that for the 3-position of both the OR3 and ZC(Z)R3 moieties, that the R3 may also include hydrogen.
Preferably, the R4 moiety is an unsubstituted or substituted phenyl moiety. More preferably, R4 is phenyl or phenyl substituted at the 4-position with fluoro and/or substituted at the 3-position with fluoro, chloro, C1-4 alkoxy, methanesulfonamido or acetamido, or R4 is a phenyl di-substituted at the 3,4-position independently with chloro or fluoro, more preferably chloro. Most preferably, R4 is 4-fluorophenyl.
In Formula (I), Z is suitably oxygen or sulfur.
Suitably, R2 is hydrogen, (CR10R23)nOR9, (CR10R23)nOR11, C1-10alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C3-7cycloalkylC1-10 alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10alkyl, heterocyclyl, heterocyclylC1-10 alkyl, (CR10R23)nS(O)mR18, (CR10R23)nNHS(O)2R18, (CR10R23)nNR13R14, (CR10R23)nNO2, (CR10R23)nCN, (CR10R23)nS(O)mxe2x80x2NR13R14, (CR10R230)nC(Z)R11, (CR10R23)nOC(Z)R11, (CR10R23)nC(Z)OR11, (CR10R23)nC(Z)NR13R14, (CR10R23)nC(Z)NR11OR9, (CR10R23)nNR10C(Z)R11, (CR10R23)nNR10C(Z)NR13R14, (CR10R23)nN(OR6)C(Z)NR13R14, (CR10R23)nN(OR6)C(Z)R11, (CR10R23)nC(xe2x95x90NOR6)R11, (CR10R23)nNR10C(xe2x95x90NR19)NR13R14, (CR10R23)nOC(Z)NR13R14, (CR10R23)nNR10C(Z)NR13R14, (CR10R23)nNR10C(Z)OR10, 5-(R18)-1,2,4-oxadizaol-3-yl or 4-(R12)-5-(R18R19)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted.
Suitably, R23 is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 alkyl moiety, all of which may be optionally substituted as defined below.
Preferably, R2 is hydrogen, an optionally substituted heterocyclyl ring, and optionally substituted heterocyclylC1-10 alkyl, an optionally substituted C1-10 alkyl, an optionally substituted C3-7cycloalkyl, an optionally substituted C3-7cycloalkyl C1-10 alkyl, (CR10R23)nC(Z)OR11 group, (CR10R23)nNR13R14, (CR10R23)nNHS(O)2R18, (CR10R23)nS(O)mR18, an optionally substituted aryl; an optionally substituted arylC1-10 alkyl, (CR10R23)nOR11, (CR10R23)nC(Z)R11, or (CR10R23)nC(xe2x95x90NOR6)R11 group.
Preferably, R2 is selected from hydrogen, C1-10 alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC1-10 alkyl, (CR10R23)nNS(O)2R18, (CR10R23)nS(O)mR18, arylC1-10 alkyl, (CR10R23)nNR13R14, optionally substituted C3-7cycloalkyl, or optionally substituted C3-7cycloalkyl C1-10 alkyl.
When R2 is an optionally substituted heterocyclyl, the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group. When the ring is optionally substituted, the substituents may be directly attached to the free nitrogen, such as in the piperidinyl group or pyrrole ring, or on the ring itself. Preferably the ring is a piperidine or pyrrole, more preferably piperidine. The heterocyclyl ring may be optionally substituted one to four times independently by halogen; C1-4 alkyl; aryl, such as phenyl; aryl alkyl, such as benzylxe2x80x94wherein the aryl or aryl alkyl moieties themselves may be optionally substituted (as in the definition section below); C(O)OR11, such as the C(O)C1-4 alkyl or C(O)OH moieties; C(O)H; C(O)C1-4 alkyl, hydroxy substituted C1-4 alkyl, C1-4 alkoxy, S(O)mC1-4 alkyl (wherein m is 0, 1, or 2), NR10R20 (wherein R10 and R20 are independently hydrogen or C1-4alkyl).
Preferably if the ring is a piperidine, the substituents are directly attached on the available nitrogen, i.e, a 1-Formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-piperidine, 1-ethoxycarbonyl-4-piperidine. If the ring is substituted by an alkyl group and the ring is attached in the 4-position, it is preferably substituted in the 2- or 6-position or both, such as 2,2,6,6-tetramethyl-4-piperidine.
When R2 is an optionally substituted heterocyclyl C1-10 alkyl group, the ring is preferably a morpholino, pyrrolidinyl, or a pipedidinyl group. Preferably this alkyl moiety is from 1 to 4, more preferably 3 or 4, and most preferably 3, such as in a propyl group. Preferred heterocyclic alkyl groups include but are not limited to, morpholino ethyl, morpholino propyl, pyrrolidinyl propyl, and piperidinyl propyl moieties.
When R2 is an optionally substituted C3-7cycloalkyl, or an optionally substituted C3-7cycloalkyl C1-10 alkyl, the cycloalkyl group is preferably a C4 or C6 ring, most preferably a C6 ring, which ring is optionally substituted. The cycloalkyl ring may be optionally substituted one to three times independently by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; OC(O)Rb, C1-10 alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1, or 2, such as methylthio, methylsulfinyl or methylsulfonyl; S(O)maryl; cyano, nitro, amino, mono and di-substituted amino, such as in the NR7R17 group, wherein R7 and R17 are as defined in Formula (I), or where the R7R17 may cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from oxygen, sulfur or NR15; N(R10)C(O)X1 and X1 is C1-4 alkyl, aryl or arylC1-4alkyl; C1-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; optionally substituted alkyl wherein the substituents are halogen, (such as CF3), hydroxy, nitro, cyano, amino, mono and di-substituted amino, such as in the NR7R17 group, S(O)m alkyl and S(O)m aryl, wherein m is 0, 1 or 2; optionally substituted alkylene, such as ethylene or propylene; optionally substituted alkyne, such as ethyne; C(O)OR11, such as the free acid or methyl ester derivative; the group Re; C(O)H; =O; xe2x95x90Nxe2x80x94OR11; N(H)xe2x80x94OH (or substituted alkyl or aryl derivatives thereof on the nitrogen or the oxime moiety); N(ORf)xe2x80x94C(O)xe2x80x94R21; an optionally substituted aryl, such as phenyl; an optionally substituted arylC1-4alkyl, such as benzyl of phenethyl; an optionally substituted heterocycle or heterocyclic C1-4alkyl, and further these aryl, arylalkyl, heterocyclic, and heterocyclic alkyl moieties are optionally substituted one to two times by halogen, hydroxy, C1-10 alkoxy, S(O)m alkyl, cyano, nitro, amino, mono and di-substituted amino, such as in the NR7R17 group, an alkyl, or an halosubstituted alkyl.
Suitably Re is a 1,3-dioxyalkylene group of the formula xe2x80x94Oxe2x80x94(CH2)sxe2x80x94Oxe2x80x94, wherein s is 1 to 3, preferably s is 2 yielding a 1,3-dioxyethylene moiety, or ketal functionality.
Suitably Rf is hydrogen, a pharmaceutically acceptable cation, aroyl or a C1-10 alkanoyl group.
Suitably R21 is NR22R24; alkyl1-6; halosubstituted alkyl1-6; hydroxy substituted alkyl1-6; alkenyl2-6; aryl or heteroaryl optionally substituted by halogen, alkyl1-6, halosubstituted alkyl1-6, hydroxyl, or alkoxy1-6.
Suitably R22 is H or alkyl1-6.
Suitably R24 is H, alkyl1-6, aryl, benzyl, heteroaryl, alkyl substituted by halogen or hydroxyl, or phenyl substituted by a member selected from the group consisting of halo, cyano, alkyl1-12, alkoxy1-6, halosubstituted alkyl1-6, alkylthio, alkylsulphonyl, or alkylsulfinyl; or R22 and R24 may together with the nitrogen to which they are attached form a ring having 5 to 7 members, which members may be optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen. The ring may be saturated or contain more than one unsaturated bond. Preferably R21 is NR22R24 and R22 and R24 are preferably hydrogen.
When the R2 cycloalkyl moiety is substituted by NR7R17 group, or NR7R17 C1-10 alkyl group, and the R7 and R17 are as defined in Formula (I), the substituent is preferably an amino, amino alkyl, or an optionally substituted pyrrolidinyl moiety.
A preferred position of ring substitution on the C6 cycloalkyl moiety is the 4-position. When the cycloalkyl ring is di-substituted it is preferably di-substituted at the 4 position, such as in: 
wherein R1xe2x80x2 and R2xe2x80x2 are independently the optional substituents indicated above for R2. Preferably, R1xe2x80x2 and R2xe2x80x2 are hydrogen, hydroxy, alkyl, substituted alkyl, optionally substituted alkyne, aryl, arylalkyl, NR7R17, and N(R10)C(O)R11. Suitably, alkyl is C1-4 alkyl, such as methyl, ethyl, or isopropyl; NR7R17 and NR7R17 alkyl, such as amino, methylamino, aminomethyl, aminoethyl; substituted alkyl such as in cyanomethyl, cyanoethyl, nitroethyl, pyrrolidinyl; aryl such as in phenyl; arylalkyl, such as in benzyl; optionally substituted alkyne, such as ethyne or propynyl; or together R1xe2x80x2 and R2xe2x80x2 are a keto functionality.
For compounds of Formula (I), s is 0, or an integer having a value of 1 to 5.
For compounds of Formula (I), t is 0 or an integer having a value of 1 to 3. This results in a 4 to 7 membered cycloalkenyl ring which is optionally substituted by the R2 moiety.
For compounds of Formula (I), Rg is independently hydrogen or R2.
In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly attached to the nitrogen, oxygen or sulfur moieties, for instance in OR3, or for certain R2 moieties.
Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
As used herein, xe2x80x9coptionally substitutedxe2x80x9d, unless specifically defined, shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted C1-10alkyl; C1-10 alkoxy, such as methoxy or ethoxy; S(O)m alky), wherein m is 0, 1 or 2, such as methylthio, methylsulfinyl or methylsulfonyl; halosubstituted C1-10 alkoxy; amino, mono and di-substituted amino, such as in the NR7R17 group; or where the R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S; C1-10 alkyl, cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; halosubstituted C1-10 alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl moieties may also be substituted one to three times by halogen; hydroxy; hydroxy substituted alkyl; C1-10 alkoxy; S(O)m alkyl; amino, mono and di-substituted amino, such as in the NR7R17 group; alkyl, or CF3.
The following terms, as used herein, refer to:
xe2x80x9chaloxe2x80x9d or xe2x80x9chalogensxe2x80x9d, include the halogens: chloro, fluoro, bromo and iodo.
xe2x80x9cC1-10alkylxe2x80x9d or xe2x80x9calkylxe2x80x9dxe2x80x94both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
The term xe2x80x9ccycloalkenylxe2x80x9d is used herein to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one bond including but not limited to cyclopentenyl, cyclohexenyl, and the like.
The term xe2x80x9calkenylxe2x80x9d is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
xe2x80x9carylxe2x80x9dxe2x80x94phenyl and naphthyl.
xe2x80x9cheteroarylxe2x80x9d (on its own or in any combination, such as xe2x80x9cheteroaryloxyxe2x80x9d, or xe2x80x9cheteroaryl alkylxe2x80x9d)xe2x80x94a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, indole, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
xe2x80x9cheterocyclicxe2x80x9d (on its own or in any combination, such as xe2x80x9cheterocyclylalkylxe2x80x9d)xe2x80x94a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cheterocyclicalkylxe2x80x9d is used herein to mean C1-4 alkyl as defined above attached to an aryl, heteroaryl or heterocyclic moiety as also defined herein unless otherwise indicate.
xe2x80x9csulfinylxe2x80x9dxe2x80x94the oxide S(O) of the corresponding sulfide, the term xe2x80x9cthioxe2x80x9d refers to the sulfide, and the term xe2x80x9csulfonylxe2x80x9d refers to the fully oxidized S(O)2 moiety.
xe2x80x9caroylxe2x80x9dxe2x80x94a C(O)Ar, wherein Ar is as phenyl, naphthyl, or aryl alkyl derivative such as defined above, such group include but are note limited to benzyl and phenethyl.
xe2x80x9calkanoylxe2x80x9dxe2x80x94a C(O)C1-10 alkyl wherein the alkyl is as defined above.
It is recognized that the compounds of the present invention may exist as stereoisomers, regioisomers, or diastereiomers. These compounds may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are included within the scope of the present invention.
Synthetic Methods
The compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in Scheme I below. The synthesis provided for in these Schemes is applicable for producing compounds of Formula (I) having a variety of different R1, R2, and R4 groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the nucleus has been established, further compounds of Formula (I) may be prepared by applying standard techniques for functional group interconversion all well known in this art.
Compounds of Formula (I) are cycloalkylene derivatives which may be readily prepared using procedures well known to those of skill in the art and may be prepared by analogous methods to those indicated herein below. 
Suitable protecting groups for use in the present invention, are well known in the art and described in many references, for instance, Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981.
Pharmaceutically acid addition salts of compounds of formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid in the presence of a suitable solvent.